Allergic rhinitis is the sixth most common chronic condition in the United States, outranking heart disease. Between 5 and 22% of the United States population are estimated to have allergies--40 million people being a median estimate. Some allergy victims experience only mild and seasonal symptoms, yet others experience severe, almost continuous symptoms. Incidence of allergy is equally as common for either sex. Evidence predicts genetic predisposition to allergic disorders, such as, for example, asthma, rhinitis, urticaria, and eczema.
The allergic response is classified by three stages: 1) a sensitization stage; 2) an immediate hypersensitivity reaction; and 3) a late phase hypersensitivity reaction. Sensitization occurs when an allergen first enters the body. The allergen causes no overt symptoms, but instead it prepares the body to react promptly to future encounters with the allergen. During sensitization, macrophages phagocitize, process and present the allergen on their surface, activating helper T cells. Activated T cells produce interleukin-4 (IL-4), which is necessary for IgE production by B cells. IgE production also requires physical interaction of CD40, expressed on the surface of B cells, with CD40L, a CD40 ligand expressed on the surface of T cells.
IgE synthesized by B cells in response to initial exposure to allergen then binds to its high affinity receptor, Fc.epsilon.RI, which is expressed on the surface of mast cells and basophils, thus priming the body for its next encounter with allergen.
Subsequent contact with the allergen induces an immediate hypersensitive reaction. Allergen cross-links IgE bound to its receptor on mast cells, initiating activation of multiple kinases, which results in rapid changes in protein phosphorylation. Eiseman et al., Nature, vol. 355, 78-80 (1992) and Li et al., Mol. Cell Biol., vol. 12, 3176-3182 (1992).
In one event triggered by this response, tyrosine phosphorylation of phospholipase C.gamma.1 (PLC.gamma.1) increases hydrolysis of phosphatidylinositol to inositol triphosphates and DAG, in turn increasing intracellular levels of calcium, and activates protein kinase C (PKC). Park et al., J Biol. Chem., vol. 266, 24237-24240 (1991).
Other enzymatic activities implicated as components of the allergic response include: hydrolysis of phosphatidylcholine (PC) to phosphatidic acid (PA) by phospholipase D (PLD); dephosphorylation of PA to DAG by phosphatidic acid phosphohydrolase (PAPH); activation of protein kinase C (PKC) by DAG; the release of arachadonic acid from phopholipids by phospholipase A.sub.2 (PLA.sub.2); metabolism of arachidonic acid by cyclooxygenase and lipoxynase to form prostaglandins and leukotreines; regulation of calcium influx by G proteins; and post-translational isoprenylation of proteins. This sequence of events ultimately results in degranulation, and the synthesis and secretion of prostaglandins and leukotreines. Lin et al., Biochem J., vol. 287, 325-331 (1992) and Ozawa et al., J. Biol. Chem., vol. 268, 1749-1756 (1993).
During the late phase hypersensitivity reaction, mast cells recruit, prime and activate other cells, such as neutophils, macrophages, basophils and eosinophils, by secreting cytokines and chemokines. Some cytokines that are produced, such as interleukin-3 (IL-3)--a mast cell growth factor-, IL-4(an IgE "switch factor"), IL-5 (an eosinophil differentiation factor), and interleukin-6 (IL-6)--a factor controlling immunoglobulin secretion, are known to be produced by a subset of T cells, Th2 cells. Other cytokines include interleukin-1(IL-1), tumor necrosis factor (TNF.alpha.), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.gamma.(INF-.gamma.), JE, macrophage inhibitory peptide-1.alpha.(MIP1.alpha.) and macrophage inhibitory peptide-1 .beta.(MIP1.beta.). Plaut et al., Nature, vol. 339, 64-67 (1989) and Burd et al., J Exp Med, vol. 170, 245-257 (1989).
In addition to producing IL-4, mast cells and basophils also express the ligand (CD40L) to the CD40 receptor, permitting direct regulation of IgE production independent of T cells. Gauchat et al., Nature, vol. 365, 340-343 (1993). In turn, many of the cells recruited to the inflammation site produce their own cytokines as well as histamine-releasing factors, causing a corresponding release of histamine. Activating and recruiting additional inflammatory cells to the initial contact site escalates and prolongs the inflammatory response.
For one particularly prevelent disease, asthma, estimates predict that 4 to 5 percent of the population in the United States, approximately 10 million people, suffer from its symptoms. Inadequate asthma therapies have, in part contributed to increased morbidity and mortality associated with this disease. Statistically, allergic asthma accounts for 90% of all asthmatic conditions in victims under 16 years old, 70% of asthmatic conditions in victims under 30 years old, and 50% of asthmatic conditions in those over 30 years old.
Asthma is a chronic illness characterized by episodic coughing, wheezing, chest tightness, and dyspnea. Allergen such as, ozone and tobacco, microorganisms, exercise or stress are some of the many causes of asthma. Much like an allergic response, asthma has an early and late phase response. Acute symptoms of the early phase usually peak in 30 to 60 minutes and then resolve within a few hours, either spontaneously or with treatment. Inflammatory events of the late phase usually peak in 5 to 6 hours and last from several hours to several days.
In allergic asthma, as in an allergic response, allergen cross-links IgE receptors on mast cells, triggering an early phase, asthmatic response. Activated mast cells then release histamine and other inflammatory mediators. Some pathologic consequences of histamine and inflammatory mediator release are: impaired bronchial smooth muscle contraction, heightened vascular permeability, epithelial damage, and vasodilation. Clinically, the symptoms are bronchospasm, mucus secretion, and edema. The late phase response is characterized by infiltration of eosinophils, neutrophils, and other inflammatory cells, coupled with secretion of highly viscous mucus.
Approximately 50% of all adults with early phase, allergen response will have a late phase response. Thus, if an early phase response were inhibited, likelihood of a late phase response occurring would be severely diminished. The various early events in the allergic response (discussed above) have therefore been of significant interest in investigations aimed at finding therapies that would inhibit or prevent both an early and late phase response.
Research has shown that an immediate consequence of IgE-primed Fc.epsilon.RI engagement by allergen on mast cells results in signal transduction through a second messenger pathway. The inventive method for inhibiting an allergic response makes use of compounds that inhibit allergen-stimulated Fc.epsilon.RI signal transduction.